Mycobacterial Cell Wall-DNA Complex in Treatment of BCG-refractory Patients With Non-muscle Invasive Bladder Cancer

Bioniche Life Sciences Inc.
Study Design: 
Phase II/III, single arm trial of mycobacterium phlei cell wall – nucleic acid complex (MCNA) in patients with non-muscle invasive bladder cancer (high grade papillary tumors and/or CIS) who are refractory to BCG therapy. Patients treated with an induction course followed by maintenance therapy up to 2 years. The primary endpoint was 1-year DFS and secondary endpoints were duration of disease-free survival (DFS), progression-free survival (PFS), and overall survival.
MCNA is a nonpathogenic and nonviable strain of mycobacterium that may potentially offer the benefits of BCG without the potential toxicity. Furthermore, it may be a viable substitute for BCG shortages.
After publishing the results, the drug was presented to a FDA panel for a biologics license application and voted down 18-6. Unfortunately the primary endpoint fell short of the intended result (1 year DFS ≥ 40%). Furthermore, the FDA calculated the true DFS to be 20.9% at 1 year. In the FDA analysis, DFS in CIS-containing patients was also evaluated separately as the absence of tumor in these patients is unlikely to result from bladder biopsy/TURBTs (as opposed to papillary tumors). By looking at only CIS containing tumors, DFS did not appear as robust (18.8% DFS at 1 year). Finally, we now know that the intended endpoint of improvement in DFS was much higher than it needed to be as an absolute improvement of 10-15% in BCG-unresponsive patients may be clinically significant. The two main learning points were a) that studies should enrich their population with CIS-containing patients and b) that studies should aim for an absolute improvement of 10-15% over historical controls in endpoints even though this will require the enrollment of more patients.
Overall DFS was 25% at 1 year and 19% at 2 years. PFS was 87.3% at 1 year. The median time to cystectomy was 263 days in MCNA responders vs. 174 days in non-responders. Overall, 15 patients (11.6%) developed metastatic bladder cancer.